CD8+ T cells are known to control infections， but their role in preventing latent infection from establishing has not been thoroughly investigated. We hypothesized that a potent CD8+ T cell response patrolling the mucosal viral entry points could kill the first infected cells and thereby abrogate the infection before latency is established. To investigate this， replication deficient adenovirus serotype 5 vectors encoding murine γ-herpesvirus-68 CD8+ T cell epitopes linkedto the T cell adjuvant Invariant chain， were developed. We show that intranasal vaccination of mice reduces the risk of establishment of latent infection from multiple intranasal ID50 challenges with murine γ-herpesvirus-68 by 81% per exposure at 14?days post vaccination. Protection waned over time， but immune responses were extended by heterologous prime-boost vaccination applied simultaneously intramuscularly and intranasally， and animals vaccinated 66?days prior to challenge showed a strong trend of long-term protection. Our data provides evidence that CD8+ T cells are able to protect against establishment of latent infection. Although the protective efficacy is difficult to maintain over time， this proof-of-concept study suggests a role for a CD8+ T cell arm in future vaccine strategies against latent human viral infections caused by pathogens such as HIV and multiple herpes virus.